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BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

Lenalidomide is manageable and effective in multiple myeloma, particularly in elderly patients. Surprisingly, the combination of lenalidomide with rituximab produced clinically significant anemia at 25 mg/day for 21/28 days, the highest possible dose, in Waldenstrom's Macroglobulinemia (WM). We aimed to determine the maximum tolerated dose (MTD) of single agent lenalidomide and determine its impact on WM. RV-WM-0426 is a multicenter dose escalation open label phase 1/2 study of lenalidomide in relapsed/refractory WM (RRWM). Lenalidomide was given orally 21/28 days per cycle for 1 year, at escalated dose of 15 to 20 mg during phase 1 to determine the MTD; the phase 2 part was conducted at the MTD. Seventeen RRWM patients were included. The MTD was established at 15 mg/day 21/28. By ITT analysis, the overall response rate was 29%. With a median follow-up of 36 months, median TTP was 16 months (95% CI 5.5-26), the 5-year OS was 91%. The most frequent adverse events ≥ grade 3 at 15 mg were 14% anemia and 43% neutropenia. The MTD of lenalidomide is 15 mg/day 21/28 days in RRWM. Lenalidomide is active in the treatment of RRWM and the safety profile appears manageable. Future studies may look into combinations of lenalidomide and continuous dosing.

Background aims This study aimed to characterize the immune effectors contained in apheresis samples obtained from patients with grafts mobilized with plerixafor and granulocyte colony-stimulating factor (G-CSF) (P+G) compared with grafts mobilized with G-CSF alone (G). Methods Aliquots of apheresis samples were obtained from 36 patients with malignant diseases after mobilization with G (n = 18) or P+G (n = 18). The phenotype and cytokine secretion profile of T cell and dendritic cell subsets were characterized by multicolor cytometry including intracellular cytokine staining. Results In grafts collected after mobilization with P+G, there was a significantly higher percentage of CD3 + T cells compared with samples collected after mobilization with G alone. On a functional level, a significant increase of interferon-γ and tumor necrosis factor-α secreting CD8 + T cells was observed in the P+G group compared with the G group. CD4 + Foxp3 + regulatory T cells were similar in both groups but exhibited a lower expression of inducible costimulatory molecule and a significantly higher expression of CD127 in the P+G group. Myeloid dendritic cells (MDCs) and BDCA3 + dendritic cells were similar in both groups. In contrast, plasmacytoid dendritic cells (PDCs) (CD123 + BDCA2 + HLA-DR + ) were significantly increased in the P+G grafts, leading to a higher PDC-to-MDC ratio. PDCs mobilized by P+G displayed different functional markers—a higher percentage of ILT7 + PDCs and decreased expression of CD86—suggesting a potential regulatory capacity of PDCs mobilized by P+G. Conclusions Grafts mobilized with P+G exhibited major different functional features compared with grafts mobilized with G alone, suggesting that such grafts may have an impact on patient outcome after autologous stem cell transplantation.

Lenalidomide is manageable and effective in multiple myeloma, particularly in elderly patients. Surprisingly, the combination of lenalidomide with rituximab produced clinically significant anemia at 25 mg/day for 21/28 days, the highest possible dose, in Waldenström's Macroglobulinemia (WM). We aimed to determine the maximum tolerated dose (MTD) of single agent lenalidomide and determine its impact on WM. RV-WM-0426 is a multicenter dose escalation open label phase 1/2 study of lenalidomide in relapsed/refractory WM (RRWM). Lenalidomide was given orally 21/28 days per cycle for 1 year, at escalated dose of 15 to 20 mg during phase 1 to determine the MTD; the phase 2 part was conducted at the MTD. Seventeen RRWM patients were included. The MTD was established at 15 mg/day 21/28. By ITT analysis, the overall response rate was 29%. With a median follow-up of 36 months, median TTP was 16 months (95% CI 5.5-26), the 5-year OS was 91%. The most frequent adverse events ≥ grade 3 at 15 mg were 14% anemia and 43% neutropenia. The MTD of lenalidomide is 15 mg/day 21/28 days in RRWM. Lenalidomide is active in the treatment of RRWM and the safety profile appears manageable. Future studies may look into combinations of lenalidomide and continuous dosing.

This study addressed the question of upfront allo-SCT in untreated PTCL patients (n = 49). The 2-year OS rate was 59% but 72.5% for transplanted patients (n = 29). Disease status at the time of transplantation was predictive marker for PFS/OS. This work shows that upfront allo-SCT is feasible with low TRM and provide long-term disease control in PTCLs but one-third of patients is chemo-refractory. Background Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous diseases with dismal outcome when treated with chemotherapy alone. Because allogeneic stem-cell transplantation (allo-SCT) can cure relapse/refractory patients, we hypothesized that upfront allo-SCT may provide a better outcome. Therefore, all patients that presented with advanced PTCL in our institution at diagnosis were scheduled to undergo upfront allo-SCT after induction chemotherapy. Patients and methods The aim of the present work was to assess the feasibility and toxicity of upfront allo-SCT. From 2004 to 2012, 49 newly diagnosed PTCL patients were scheduled to receive upfront allo-SCT. A human leukocyte antigen-matched donor was found for 42 patients: related to the patient in 15 cases, unrelated in 20 cases, and suitable cord blood units were used in 7 cases. Results After induction chemotherapy, 17 patients reached complete remission and 29 (60%) proceeded to upfront allo-SCT. For all patients, the 1 and 2-year overall survival (OS) rates were 59% [95% confidence interval (CI) 47–75] and 55% (95% CI 43–71), respectively. The most frequent reason we did not proceed to allo-SCT was disease progression or insufficient response after induction. For transplanted patients, the 1- and 2-year OS were 76% (95% CI 62–93) and 72.5% (95% CI 58–91), respectively. Toxicity-related mortality (TRM) 1 year after allo-SCT was only 8.2% (95% CI 0–18.5). The 2-year progression-free survival (PFS) rate of patients who did not proceed to allo-SCT (n = 20) was below 30%. The disease status at the time of transplantation was a strong predictive marker for both PFS and OS in transplant patients. Conclusions Upfront allo-SCT in PTCLs is feasible with low TRM, and it provides long-term disease control. However, one-third of patients remain chemo-refractory and, thus, new therapeutic approaches are warranted. The role of upfront allo-SCT compared with other therapeutic approaches in PTCLs requires investigation in randomized studies.

Purpose: Intrinsic activation of nuclear factor κB (NF-κB) characterizes various hematologic malignancies. In this study, we specifically address the role of NF-κB blockade in mediated antimyeloma activity using the IκB kinase-2 pharmacologic inhibitor, AS602868.Experimental Design: Human myeloma cell lines (n = 16) and primary myeloma cells (n = 10) were tested for their sensitivity to AS602868 in terms of proliferation and apoptosis. Both in vitro and in vivo experiments were conducted. Functional mechanisms regarding the apoptotic pathways triggered by AS602868 were studied. The potential proapoptotic synergy between AS602868 and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) was also evaluated.Results: Our results show that AS602868 efficiently targeted the canonical NF-κB pathway in myeloma cells and potently inhibited their growth in inducing apoptosis through Bax and caspase-3 activation. AS602868 also induced apoptosis in primary myeloma cells even in the presence of bone marrow mononuclear cells. Moreover, the IκB kinase-2 inhibitor targeted the paracrine effect on the bone marrow environment. Indeed, it decreased the intrinsic and myeloma-induced secretion of interleukin-6 from bone marrow stromal cells. In addition, AS602868 inhibited myeloma cell growth in the MM.1S xenograft myeloma model. Of particular interest, AS602868 strongly increased myeloma sensitivity to TRAIL in blocking TRAIL-induced NF-κB activation and in decreasing the expression of antiapoptotic proteins such as cFLIP and cIAP-1/2.Conclusions: Taken together, our data point out the interest to inhibit the canonical NF-κB pathway in myeloma and clearly encourage clinical evaluation of novel therapies based on targeting NF-κB, especially in combination with TRAIL.

A critical role for vascular endothelial factor (VEGF) has been demonstrated in multiple myeloma (MM) pathogenesis. Here, we characterized the effect of the small-molecule VEGF receptor inhibitor pazopanib on MM cells in the bone marrow milieu. Pazopanib inhibits VEGF-triggered signaling pathways in both tumor and endothelial cells, thereby blocking in vitro MM cell growth, survival, and migration, and inhibits VEGF-induced up-regulation of adhesion molecules on both endothelial and tumor cells, thereby abrogating endothelial cell-MM cell binding and associated cell proliferation. We show that pazopanib is the first-in-class VEGF receptor inhibitor to inhibit in vivo tumor cell growth associated with increased MM cell apoptosis, decreased angiogenesis, and prolonged survival in a mouse xenograft model of human MM. Low-dose pazopanib demonstrates synergistic cytotoxicity with conventional (melphalan) and novel (bortezomib and immunomodulatory drugs) therapies. Finally, gene expression and signaling network analysis show transcriptional changes of several cancer-related genes, in particular c-Myc. Using siRNA, we confirm the role of c-Myc in VEGF production and secretion, as well as angiogenesis. These preclinical studies provide the rationale for clinical evaluation of pazopanib, alone and in combination with conventional and novel therapies, to increase efficacy, overcome drug resistance, reduce toxicity, and improve patient outcome in MM.

Background. Lenalidomide has proved safe and effective in multiple myeloma (MM), particularly in elderly patients. Furthermore, it has been showed that lenalidomide enhanced rituximab-mediated antibody-dependent cell-mediated cytotoxicity. Unexpectedly, lenalidomide (25 mg/d on days 21/28) along with rituximab (375 mg/m²/wk) produced clinically significant acute anemia in patients with WM, most of them received 25mg/day with no improvement when the dose was reduced (Treon et al. CCR, 2009). No cause was attributable to the occurrence of this adverse event. Thus, we sought to perform a study with incremental concentrations of single agent lenalidomide to determine the maximum tolerated dose (MTD) of lenalidomide in WM, and possibly unravel the cause of anemia upon treatment with lenalidomide. Methods. RV-WM-0426 is a multicenter phase I/II dose escalation open label study of lenalidomide in relapse/refractory WM. Lenalidomide was given oral daily 21 / 28 days per cycles for 1 year, at escalated dose of 15 to 20 then 25mg across cohorts of 3 to 6 patients each during the phase 1 part, then followed by 9 patients to recruit in the phase 2 part at the maximum tolerated dose (MTD). The primary endpoint was the MTD, secondary endpoint included response rate (International WM Workshop) and response duration, safety, measurements of free light chain assays, and PFS and OS. Results. 17 patients were enrolled in the study, the median age was 69 (range 48-81), with 7 patients older than 75, 70% were male. 53% had adverse IPSS 3. The median hemoglobin level was 11.2 (95%CI 9.9-12.5), median M spike level 26.5 (95%CI 23-40), 23% had clearance creatinin below 60ml/min. The median number of prior lines was 1 (range 1-8), all patients but 2 exposed to alkylating agents, 30% to nucleoside analogues, 47% to the monoclonal antibody mabthera, none of the patients have had a transplantation. The median time from diagnosis to study entry was 3 years (range 2-15). At the highest dose tested, 20 mg, 2 patients had dose-limiting toxicity, septic syndrome during grade 4 neutropenia and severe fatigue, respectively. The MTD was thus established at the 15 mg/day 21 days out of 28. 7/17 (41%) patients completed one year of single agent lenalidomide at 15mg day 21/28. Single agent lenalidomide in WM provided an overall response (minimal response (MR) and better) on an intent-to-treat basis at 15mg/day of 36%, and an extra 2 patients had a prolonged stable disease (SD). A flare effect (transient initial increase of the M spike) was observed in 5 patients. With a median follow-up of 36 months, 14 have progressed with a median time to progression of 16 months (95%CI 5.5-26), with 35% of patients with a PFS greater than 24 months. One patient died with a 5-year overall survival (OS) of 91%. The most common adverse event (AE ≥ 10%) was fatigue of at least grade 2, reported in 50% of the patients. The incidence rate of grade 3 and greater hematological AE at 15mg was 14% for anemia, 43% for neutropenia, and no thrombopenia observed. 78% experienced a non hematological AE of at least grade 2, but only 2 patients had a grade 3 AE, nephrotic syndrome and cramps. No second primary malignancy (SPM) nor thromboembolic event were reported to date. Only 21% of patients had dose reduction with a median time of 7 months, and 35% had study drug interruption related to an AE with a median time of 4 months. Conclusion. The MTD of lenalidomide is 15mg/day given on days 21/28 in relapse and refractory WM. Lenalidomide is active in the treatment of RRWM and the safety profile appeared manageable, essentially of grade 2 AEs. Future studies may look into combinations to lenalidomide and continuous therapeutic effect in WM at the determined MTD. Disclosures Leleu: Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding. Leblond:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Emerging evidence indicates that multiple myeloma (MM) can follow a number of evolutionary pathways over a patient’s disease course. Recently, genomic data have shown the coexistence in many patients of several tumour types, which could be either genetically stable, evolving linearly or be constituted of heterogeneous clonal mixtures with predominant clones shifting over time (Keats, Blood 2012;120:1067-1076). Little is known however of immunophenotypic evolution of the myeloma cells (MM cells) during MM progression. In a retrospective single-centre analysis of tumoral immunophenotypes, we examined sequential bone marrow or peripheral blood samples from 51 MM patients. Multiparameter flow cytometry was performed to assess MM phenotype using CD38 and CD138 expression as well as intracytoplasmic light chain usage restriction in most cases. The presence or absence of CD19, CD20, CD27, CD28, CD56 or CD117 on the MM cells’surface was investigated additionally. A median of 4 of the latter antigens was examined per sample. Most MM cells were homogeneous in the expression or absence of expression of the differentiation antigens investigated. Immunophenotype changes were defined as the loss or gain of at least 1 antigen. Whenever partial expression of one or several antigens was observed on MM cells, indicating MM subsets, the presence of subclones was suspected. Samples were obtained at diagnosis and relapse for 33 MM patients, and during consecutive relapses for 18. The total amount of analysed samples was 109, with a median of 2 samples per patient (range: 2-3). A modification of immunophenotype occurred in 22 patients (43%), with one antigen change (68%), two antigens changes (18%) or three antigens changes (14%). Immunophenotypic changes are summarized in table 1. For 20% of the cases or more, this involved CD28 (n=11, balanced gain or loss) or CD27 (n=7, mostly loss). CD56 expression, scarcely negative on the first assessment, was gained at relapse in three cases. Other antigens were expressed in a stable fashion over time. Eighteen (35%) of the patients had at least a subclone on the first immunophenotype, which was lost and/or modified in 14 / 18 patients at time of subsequent relapse. There was no significant impact of immunophenotypic modifications on overall survival rates Similarly, the presence of a subclone at first examination, or the immunophenotypic change of this subclone over time was not associated with differences in overall survival rates. In conclusion, this retrospective single centre study demonstrates that the immunophenotype of MM cells is mostly stable during the course of the disease. When changes occur, they do not seem to affect the clinical course of the patients. These preliminary results need confirmation on a larger and prospective trial. Disclosures: No relevant conflicts of interest to declare.

Abstract 956 Background. Unrelated umbilical cord blood cells (UCB) have emerged as an alternative stem cell source for allo-SCT in patients who lack a matched-related or unrelated donor (MUD). Several studies found a similar outcome between HLA 4–6/6 matched UCB and HLA 8/8 matched and 7/8 mismatched unrelated donors, mainly in the setting of standard myeloablative conditioning. However, currently it is more common practice in many centres to search for 10/10 or 9/10 MUD or for double UCB. Thus far, no study focussed on the comparison of outcome of patients who received double UCB allo-SCT versus allo-SCT using 9/10 mismatched donors. With this background, this retrospective analysis assessed outcome after allo-SCT using double UCB cells or 9/10 mismatched donors in the setting of a RIC regimen. Patients and Methods. This analysis was performed in a series of 152 consecutive adult patients treated for hematological malignancies in 2 centers adopting similar transplant procedures. 85 patients were males (56%) and the median age at time of allo-SCT was 53 years (range, 16–69). Diagnoses included 59 AML (39%), 21 MDS/MPN (14%), 42 NHL (28%), 5 Hodgkin diseases (3%), 18 ALL (12%) and 7 Myelomas (5%). 35 patients (23%) had standard risk disease and 117 patients (77%) presented with high risk disease. Conditioning regimen consisted of fludarabine, cyclophosphamide and low dose TBI for 108 patients (71%), fludarabine and busulfan for 35 patients (23%); and other regimens in the remaining 9 patients (6%). 50 patients (33%) received antithymocyte globulin. The donor was double UCB in 110 cases (“dUCB” group) and 9/10 mismatched unrelated in 42 cases (“9/10” group). During the study period, both participating centers adopted the same strategy for donor search and choice: in the absence of matched-related siblings or 10/10 MUD, 9/10 donors were searched. UCB cells were used if no 9/10 donor could be identified within a reasonable time frame (usually 2–3 months after search initiation). Results. With a median follow-up of 30.3 months (range, 6–72.4), the Kaplan-Meier estimate of overall survival (OS) at 2 years was comparable between both groups [52% (95%CI, 42–61%) in the dUCB group versus 48% (95%CI, 32–62%) in the 9/10 group, P=0.55]. The cumulative incidence of NRM was 26% in the dUCB group versus 24% in the 9/10 group (P=0.95). Grade 3–4 acute GVHD and extensive chronic GVHD incidences were 20% versus 21.4% (P=0.83), and 6% versus 21% (P=0.02), in the dUCB group versus the 9/10 group, respectively. The cumulative incidence of relapse was 34% in the dUCB group versus 38% in the 9/10 group (P=0.63). Finally, the estimate of progression-free survival (PFS) at 2 years was 43% (95%CI, 34–52%) in the dUCB group versus 38% (95%CI, 23–53%) in the 9/10 group (P=0.55). In multivariable analysis including the most important parameters associated with outcome (patient's age at transplantation, patient's sex, diagnosis, disease status at transplantation, use of ATG, GVHD prophylaxis), the stem cell source (dUCB versus 9/10) did not have any significant impact on OS (HR=0.92 (95% CI, 0.41–2.08); P=0.86) Conclusion. These data suggest that dUCB is likely a valid alternative graft source compared to 9/10 mismatched unrelated donors in the setting of RIC allo-SCT since both donor types showed similar results in terms of OS, PFS, disease relapse, and acute GVHD incidence. However, the significantly lower incidence of extensive chronic GVHD in the dUCB group is an important and major finding, highlighting the need for a prospective randomized study in this field. Disclosures: No relevant conflicts of interest to declare.

Abstract 1926 Introduction. In the last decade, the so-called reduced intensity or reduced-toxicity conditioning (RTC) regimens prior to allo-SCT have emerged as an attractive modality to decrease allo-SCT-related toxicities and non-relapse mortality (NRM). In the context of RTC allo-SCT, IV Busulfan proved to be a key drug, because of its safety profile and potential anti-tumor activity that can allow for early disease control while waiting for the immune-mediated GVL effect. Study objective. This phase 2 prospective multicenter trial (ClinicalTrials.gov Identifier:NCT00841724) aimed to assess at one year the efficacy and safety of a “submyeloablative” conditioning regimens based on IV Busulfan 130mg/m2/d (administered as a single daily infusion over 3 hours) for 3 days (total dose equivalent to 9.6 mg/Kg), Fludarabine 30mg/m2/d for 5 days, and ATG (Thymoglobuline*) 2.5mg/Kg/d for 2 days (the “FB3” regimen) in patients with high risk hematological malignancies candidate for allo-SCT but not eligible for a standard myeloablative conditioning regimen. For GVHD prophylaxis, patients received cyclosporine alone in case of a family donor, and cyclosporine+mycophenolate mofetil in case of an HLA-matched unrelated donor (MUD: 10/10 or 9/10). Patients and transplant characteristics. Between 2008 and 2011, a total of 80 patients were included (47 males, 59%). The median age of patients at time of allo-SCT was 53 (range, 25–64) years. Diagnoses included: ALL/AML/biphenotypic acute leukemia (n=5; n=26; n=1; 40%); MDS/MPS (n=6; 8%); CLL (n=3; 4%); NHL and HD (n=24; 30%); and myeloma (n=15; 18%). At time of conditioning, 39 patients (48%) were in first CR, 14 patients (18%) were in CR2/CR3, and 27 patients (34%) were in more advanced disease phases. The donor was an HLA-identical sibling donor in 28 cases (35%) and an HLA MUD in 52 cases (65%). The stem cell source was G-CSF-mobilized PBSC in 77 cases (96%) and unmanipulated bone marrow in 3 cases (4%). Per protocol, comorbidities and performance status were comprehensively assessed at time of inclusion. The Karnofsky score was 70%, 80%, 90%, and 100% in 4 (5%), 11 (14%), 28 (35%), and 37 (46%) patients, respectively. At time of transplant, 54 patients (68%) had at least one comorbidity, while 26 patients (32%) did not have any. In this cohort, the HCT comorbidity index developed previously by Sorror et al. was 0, 1 or 2 and >2 in 27 (34%), 21 (26%) and 32 (40%) patients, respectively. Results. All patients but one engrafted. ANC>500/μL was achieved at a median of 15 (range, 10–23) days after allo-SCT, and 98% of patients had platelets >50.000/μL by day 60 after transplantation (of whom none was below 20.000/μL at any time point). The cumulative incidences of grade 2–4 and grade 3–4 acute GVHD were 32% (95%CI, 21–43%) and 9% (95%CI, 4–18%), respectively. The cumulative incidence of relapse/disease progression (RI) at one year was 26% (95%CI, 17–36%), while the cumulative incidence of NRM was 10% (95%CI, 5–18%) at one year. The Kaplan-Meier estimates of overall (OS) and progression-free survival (PFS) at one year were 71% (95%CI, 61–81%) and 64% (95%CI, 53–74%), respectively. In terms of prognostic factors for outcome, patient age, diagnosis, donor type, gender, presence or absence of comorbidities and the HCT comorbidities index, did not have any statistically significant impact on NRM, RI, PFS and OS. Only a Karnofsky score Conclusions. Results from this phase 2 prospective multicenter trial validated the safety and efficacy of a so-called reduced-toxicity conditioning regimen which could overcome the deleterious impact of comorbidities since no statistically significant impact of the HCT comorbidity index on outcome could be shown. Such FB3 regimen appears to be safe with a 10% NRM at one year in high risk patients, and exhibits an efficient disease control both in myeloid and lymphoid malignancies, warranting further investigations as part of phase 3 trials. Disclosures: Mohty: Pierre-Fabre: Consultancy, Honoraria, Speakers Bureau. Blaise:Genzyme/Sanofi: Honoraria, Research Funding; Pierre Fabre: Honoraria, Research Funding; Otsuka: Honoraria.

Abstract 685 Background: In 2004 we have shown that first-line intensive therapy plus transplantation of autologous hematopoietic stem cells lead to an improved EFS and OS over standard CHOP regimen in adults with disseminated aggressive lymphomas (NEJM 2004; 350: 1287). Then the rituximab era came. We have shown that the addition of R to the intensive therapy was feasible and might further improve the results (BBMT 2010; 16: 672). We present here the preliminary analysis of a multicenter randomized trial aiming at comparing the results of R- CHOP every 14 days to R- HDT in adults with untreated confirmed DLBCL (clinical trial.gov: NCT 00561379). Methods: The patients were 18 to 60 y.o. with CD20 + DLBCL Ann Arbor stage 1 or 2 with bulk >/= 7 cm or 3 and 4 were randomized at diagnosis (with a stratification according to age adjusted IPI) between R-CHOP every 14 days at standard doses (8 consecutive courses if a response was observed after the first 4 courses) and R-HDT. This program consisted of 2 courses of high-dose CHOP-like regimen, 15 days apart, with rituximab (375/mg/m2) on day 1 of each course, followed by rituximab on d 22, harvest of G-CSF mobilised peripheral blood stem cells on d 28,29, then rituximab on d 36 followed by a course of high-dose methotrexate with cytarabin. For patients who achieved at least a partial response after these 3 courses, a BEAM regimen started on d 66 to 80 followed by the infusion of stem cells. In each arm, the intermediate evaluation of response was assessed by means of standard CT Scan and PET. Patients not achieving a PR or a negative PET were proposed a salvage Tx followed in case of response by an autologous transplantation. The main objective of the study was the EFS with an event defined as insufficient intermediate response, progression, relapse or death. Analysis was performed on intent to treat basis. Results: 331 pts were included from 01/2005 to 05/2010. 305 patients were found eligible and 286 are fully evaluable at time of this abstract, 143 in each arm. The main characteristics of the pts in the 2 arms are strictly super imposable. Overall 56% had a bulk as defined, 72% had a 3 or 4 AA stage and 58% had an aa IPI 2 or 3. The treatment as scheduled in the protocol was completed in 71% in the R-CHOP arm and 60% in the R-HDT arm. The intermediate evaluation showed exactly the same rate of response with Standard CT scan (CR + CRu: 65% and 62% following 4 courses R-CHOP and first 3 courses of R-HDT respectively). PET remained significantly more often + after the first 3 courses of R-HDT (43% vs 30% following 4xR-CHOP; p=0.03). The ORR (CR + Cru) was 78% and 71% in the R-CHOP and R-HDT arms respectively (p=0.8). With a med FU of surviving patients of 25 m, the probability of survival for the whole group of patients is 88% and 74% at 2 and 5 years. There is no significant difference according to the treatment arm in any of the aaIPI strata. The EFS with the standard CT Scan as an intermediate evaluation is 74% and 66% at 2y and 5 y with no difference according to the treatment arm in any aaIPI strata. The EFS with PET scan as an intermediate evaluation is 49% and 45% at 2y and 5 y and is statistically worse with R-HDT for aaIPI 2 and 3 pts (p=0.01). Conclusion: Based on these results, one cannot recommend first-line R-HDT as performed in that trial for adult patients with DLBCL. R-CHOP 14 is as efficient, less toxic and spares resources. Disclosures: Milpied: Roche: Membership on an entity's Board of Directors or advisory committees.

CsA is widely used as the backbone immunosuppressive agent for GVHD prevention after allo-SCT. Previous studies have demonstrated that the immunosuppressive effects of CsA (eg. inhibition of calcineurine in lymphocytes) may be correlated with CsA blood concentration, especially in the context of solid organ transplantation. This report aimed to investigate the impact of CsA concentrations in the early post allo- SCT period, on the incidence of severe acute GVHD, in 85 consecutive patients treated in a single centre between Jan. 2006 and Jan. 2008, and for whom CsA concentrations in the blood were monitored weekly after the start of infusion. 85 patients (45 males) received CsA (usually at 3 mg/Kg/d, 2 or 3 days prior to graft infusion) as a 24-h continuous infusion until hematopoietic recovery and switch to oral formulation. Dose modifications of CsA were performed to maintain adequate trough blood levels and to prevent nephrotoxicity. Patients’ and donors characteristics were as follow: median age: 51 (range, 18–67), 46 (54%) female donors, 33 (39%) myeloid malignancies, 49 (58%) lymphoid malignancies, and 3 cases of SAA. The stem cell source was PBSC in 66 (78%) patients, while bone marrow was used in 19 (22%) patients. 37 (43.5%) were transplanted from a matched related donor, and 48 (56.5%) from a matched unrelated donor. A myeloablative conditioning regimen was used in 24 (28%) patients, and 61 (72%) received a reduced intensity regimen. The median concentrations of CsA in the blood at 1, 2, 3 and 4 weeks after allo-SCT were 348 (range, 172–733), 284 (range, 137–535), 274 (range, 107–649), and 247 (37–695) ng/mL respectively. All patients engrafted at a median of 17 (range, 0–42) days after allo-SCT. With a median follow-up of 16 (range, 5–29) months, grade 2–4 acute GVHD occurred in 36 patients (42%) at a median of 29 (range, 6–100) days after allo-SCT. The incidence of severe grade 3–4 acute GVHD was 23% (95%CI, 14–32%). In this cohort, all acute GVHD risk factors (age, donor-recipient gender, CMV serostatus, ABO compatibility, diagnosis, disease status, stem cell source, donor type, conditioning regimen type, GVHD prophylaxis regimen, CsA concentrations) were assessed. In multivariate analysis, we found that higher whole-blood CsA concentration in the first week following graft infusion, and before onset of acute GVHD was the strongest parameter significantly associated with a reduced the risk of severe grade 3–4 acute GVHD (P=0.01; RR=0.24; 95%CI, 0.08–0.73). Despite its retrospective nature, these data strongly indicate a close relationship between CsA trough blood concentration during the early post allo-SCT period and the severity of acute GVHD. Inadequate or insufficient early exposures of CsA can be a serious risk for developing severe acute GVHD. Therefore, precise monitoring of CsA concentrations and achievement of a high CsA target concentration may be an effective tool to prevent the onset of severe acute GVHD.

Diffuse large cell lymphoma is the most common non-Hodgkin Lymphoma (NHL) that ranks among the most curable diffuse intermediate grade lymphomas. Most investigators have recognized that practically all patients with this cell type who are able to attain and maintain a complete response for 24 consecutive months are cured because late relapses seldom occur after this period of follow-up. However, relapses do occur late after the remission and the characteristics of patients who experience these relapses rarely have been studied especially for localized disease. From 1984 to 1996, three hundred and five patients aged more than 18 years were enrolled in a prospective multicenter study for primary treatment of localized stage I/II nodal and extra nodal high-grade NHL. The initial therapy consisted in three cycles of high dose CHOP regimen followed by involved field radiotherapy (40Gy). Of the 283 (93%) patients who obtained complete remission (CR), 36 (12.7%) patients relapsed more than 2 years after CR and 28 (9.8%) of them experienced relapse more than three years after CR. Clinical characteristics of patients at diagnosis are summarized in table 1. For the 28 patients who relapsed more than 3 years after diagnosis (group A), the median age was 55 years. There were 17 men and 11 women with predominant histology of diffuse large B cell lymphoma (n=15) and mixed small and large B-cell (n=6). Stage I disease was predominant (n=16) with normal LDH level (n=14). Extranodal disease was present in 11 patients. Most of the patients had no or one IPI risk factor at diagnosis (n=18). Relapses occurred after median CR duration of 84 (36–156) months. Seven patients (7/28; 25%) relapsed as a disseminated lymphoma and 17 of 21 patients who relapsed as a localized disease, relapsed at sites other than those of diagnosis. Only 4 patients relapsed at the same initial site of lymphoma. Nodal relapses remained the most frequent type of relapse (n=18; 64%). However, it is important to note that 10 patients experienced extranodal relapses especially in the central nervous system, the Waldeyer’s ring and the gastrointestinal tract. Three patients had multiple extranodal localisations. All relapsed patients received chemotherapy alone (n=20) or followed by autologous stem cell transplantation (n=8). CR was obtained in 13 patients (13/23; 56%), and partial response in 1 patients. Chemotherapy failed in 5 patients and 4 patients deceased from toxicities. At the last follow-up, only 8 (8/24; 33%) patients are still alive and disease free (n=5) or in relapse (n=3). Sixteen patients deceased and lymphoma was the most frequent cause of death (13/24; 54%). In conclusion, late relapses in the setting of localized high grade NHL treated with short course of chemotherapy and involved field radiotherapy are frequent. Relapses occurred frequently at different sites from the initial presentation mostly nodal and extranodal localisations are frequent. The rate of cure for relapsed patients is low and death from lymphoma remains high. The role of novel therapeutic approaches with the addition of rituximab to chemotherapy with or without radiotherapy in preventing late relapses is awaited. More data will be presented at the meeting Table 1: clinical characteristics at diagnosis

Nodal peripheral T-cell lymphomas represent a heterogeneous category, composed of three entities: anaplastic large cell lymphomas, peripheral T-cell lymphomas unspecified (PTCLu) and angioimmunoblastic T-cell lymphomas (AITL). The later entity has been recently recognized to derive from follicular helper T cells (TFH). Among PTCLu - which represents an ill-defined entity - a peculiar form with follicular growth pattern (PTCL-F) has been recently reported, and one article stated their association with t(5 ;9)(q33 ;q22) involving ITK and SYK (Leukemia2006; 20: 313–318). However, the origin of tumor cells and clinical aspects of this group of PTCL-F are still unknown. The aim of this study was to analyse a series of PTCL-F to describe their clinical and histopathological aspects, to identify their cell of origin, and their relationship with AITL. Fourty-two patients from 32 to 85 years of age with 51 biopsies were selected from three Departments of Pathology (Creteil, n=24, Nantes n=13, Vienna n=14). All patients showed histopathologic features of PTCL-F in at least one biopsy. Biopsies were classified into three categories according to predominant morphological features at low power magnification: follicular lymphoma-like (n=7), progressive transformation of germinal center-like (n=22), and AITL-like features with follicular colonization (n=19). Several cases have combinations of patterns. The neoplastic population is characterized by medium-sized cells with clear cytoplasm surrounded by IgD+ B-cells. Tumor cells are of helper T-cell immunophenotype [CD2+ (33/33 = 100%), CD3+ (45/48 = 93%), CD4+ (35/42 = 83%), CD5+ (39/39 = 100%), CD7+ (7/37 = 19%)], with frequent expression of CD10 (29/43 = 67%) and of TFH markers [PDCD-1 (32/36 = 88%), CXCL13+ (33/38 = 87%), BCL6+ (15/25 = 60%), CD57+ (9/16 = 56%)]. Scattered CD20+ B-immunoblasts (27/28 = 96%) and EBV+ cells (18/30 = 60%) are also frequently observed. Seven out of 31 patients (22%) in the 3 morphological patterns have t(5 ;9)(q33 ;q22) detected by fluorescent in situ hybridization. At prentation and/or at relapse, most patients had multiple lymphadenopathies (19/23 = 83%) and disseminated disease (stages III–IV, 22/28 = 79%). Skin lesions and B symptoms were present in 7/19 (37%) and 6/22 (27%) patients, respectively. In addition, 2 patients with sequential biopsies disclosed typical clinical & histopathological features of AITL in one episode. Our results show that this rare form of PTCL has an immunophenotype indicative of TFH origin, is associated with t(5 ;9) in a proportion of cases, shows some similarities in morphology and immunophenotype with AITL, suggesting a relationship, and generates diagnostic pitfalls, especially with atypical reactive lymphoid lesions and some B-cell lymphomas. The use of immunohistochemistry with TFH markers and molecular studies can help to make a correct diagnosis.

A critical role for vascular endothelial factor (VEGF) has been demonstrated in multiple myeloma (MM) pathogenesis. Here we characterized the effect of the novel and potent small-molecule VEGF-receptor inhibitor pazopanib on MM cells in the bone marrow milieu. Pazopanib inhibits VEGF-triggered signaling pathways in both tumor and endothelial cells, thereby blocking in vitro MM cell growth, survival, and migration; and inhibits VEGF-induced upregulation of adhesion molecules on both endothelial and tumor cells, thereby abrogating endothelial cell-MM cell binding and associated cell proliferation. We show that pazopanib is the first-in-class VEGF-receptor inhibitor to inhibit in vivo tumor cell growth associated with increased MM cell apoptosis, decreased angiogenesis, and prolonged survival in a mouse xenograft model of human MM. Low-dose pazopanib demonstrates synergistic cytotoxicity with conventional (melphalan) and novel (bortezomib, immunomodulatory drugs) therapies. Finally, gene expression and signaling network analysis show transcriptional changes of several cancer-related genes, in particular cMyc. Using siRNA, we confirm the role of cMyc in VEGF-production and -secretion, as well as angiogenesis. These preclinical studies provide the rationale for clinical evaluation of pazopanib, alone and in combination with conventional and novel therapies, to increase efficacy, overcome drug resistance, reduce toxicity, and improve patient outcome in MM.

Novel strategies in cancer therapy aim at inhibiting distinct signal transduction pathways that are aberrantly activated in malignant cells. Protein tyrosine kinases of the JAK family are associated with a number of cytokine and cytokine-like hormone receptors and regulate important cellular functions such as proliferation, survival, and differentiation. Constitutive or enhanced JAK activation has been implicated in neoplastic transformation and abnormal cell proliferation in various hematological malignancies. In multiple myeloma (MM), JAK kinases play a critical role because of their association with cytokine receptors of the IL-6/gp130 family. A novel small-molecule inhibitor was developed that shows a 100 to 1,000-fold selectivity for JAK1, JAK2, JAK3, and TYK2 relative to other kinases including Abl, Aurora, c-Raf, FGFR3, GSK3b, IGF-1R, Lck, PDGFRa, PKBb, and Zap-70. Growth of MM cell lines and primary patient cells was inhibited by this compound in a dose-dependent manner. The IL-6 dependent cell line INA-6 and derived sublines were sensitive to the drug, with IC50’s of less than 1 mM, in [3H]-thymidine uptake and a colorimetric, tetrazolium compound (MTS) based assay (CellTiter 96® Aqueous One Solution Cell Proliferation Assay, Promega, Madison, WI). Importantly, INA-6 and patient tumor cell growth was also inhibited in the presence of bone marrow stromal cells, which by themselves remained largely unaffected. Growth suppression of INA-6 correlated with a significant and dose-dependent increase in the percentage of apoptotic cells, as evaluated by Apo2.7 staining after 48 hours of drug treatment. In addition, the compound blocked IL-6 induced phosphorylation of STAT3, a direct downstream target of JAK kinases and important transcription factor triggering anti-apoptotic pathways. In other myeloma cell lines, the drug overcame the protective effect of gp130 cytokines on dexamethasone induced apoptosis. In MM1.S cells, it completely blocked IL-6 induced phosphorylation of SHP-2 and AKT, both known to mediate the protective effects of IL-6. In contrast, AKT phosphorylation induced by IGF-1 remained unchanged, demonstrating selectivity of the compound. These studies show that disruption of JAK kinase activity and downstream signaling pathways inhibits myeloma cell growth and survival as well as circumvents drug resistance, thereby providing the conceptual basis for the use of JAK kinase inhibitors as a novel therapeutic approach in MM.